The phosphatidylinositol-3-kinase (PI3K)/Akt and the mammalian target of rapamycin (mTOR) signaling pathways is one of the most frequently deregulated pathways in human cancers. This pathway controls multiple cellular processes, including metabolism, motility, proliferation, growth and survival. It can be aberrantly activated through multiple mechanisms, including diverse genomic alterations involving oncogenes and tumour suppressor genes.1.Janku F. Yap T.A. Meric-Bernstam F. Targeting the PI3K pathway in cancer: are we making headway?.Nat Rev Clin Oncol. 2018; 15: 273-291doi:10.1038/nrclinonc.2018.28Crossref PubMed Scopus (581) Google Scholar These alterations offer opportunities for therapeutic targeting of the pathway. PI3Kα protein complex is composed of regulatory (p85α) and catalytic (p110α) subunits. Pik3ca codes for p110α, which is the most frequently mutated oncogene across different cancers. Many distinct mutations have been identified, including hotspot single-amino acid substitutions in the helical (E542K and E545K) or kinase (H1047R) domains. These mutations are present in 40% of patients with luminal breast cancer (BC) and are a target for cancer therapy. In fact, several PI3K inhibitors have been developed in clinical trials. Recently, alpelisib (an oral α-specific PI3K inhibitor that selectively inhibits p110α) has been approved in combination with fulvestrant as it improved progression-free survival and overall response rate among patients with Pik3ca mutant luminal metastatic BC.2.André F. Ciruelos E. Rubovszky G. et al.Alpelisib for PIK3CA-Mutated, Hormone Receptor-Positive Advanced Breast Cancer.N Engl J Med. 2019; 380: 1929-1940doi:10.1056/NEJMoa1813904Crossref PubMed Scopus (1068) Google Scholar In early clinical trials with alpelisib, the authors observed that double Pik3ca mutations could be a biomarker candidate. For this reason, the authors undertake a deep analysis of the prevalence of double mutations and their potential biological meaning. The prevalence of double Pik3ca mutations in different public datasets across different tumours types was between 12% and 13%. Indeed, breast, uterine and colorectal cancers had the greatest number of multiple Pik3ca-mutant tumours. Double mutations were enriched in luminal BCs compared with HER2+ or triple-negative BCs (15.4% vs 5.4%, p=0.004), and occur at similar frequencies in therapy-naïve primary tumours and metastatic tumours (11.6% vs 15.7%, p=0.130). Interestingly, distinct patterns of comutation were observed. Thus, in BC, the most frequent combination was a canonical ‘major-mutant’ hotspot (involving either E542, E545 or H1047) combined with a second ‘minor-mutant’ site (involving either E453, E726 or M1043). However, in the non-BC cohorts, E88 and E93 second-site mutations were the most enriched. Most of these double mutations (68%) were clonal and mainly found as cis mutations; in other words, double Pik3ca mutations were in the same cell and in a single protein. Vasan et al3.Vasan N. Razavi P. Johnson J.L. et al.Double PIK3CA mutations in cis increase oncogenicity and sensitivity to PI3Kα inhibitors.Science. 2019; 366: 714-723doi:10.1126/science.aaw9032Crossref PubMed Scopus (122) Google Scholar showed at in vitro and in vivo models that cis Pik3ca mutants increased downstream PI3K pathway signalling and enhanced proliferation compared with single-hotspot mutants. Moreover, mutations in trans do not increase these effects more than single mutations. This hyperactivity is due to a combination of biochemical mechanisms, by which these double Pik3ca mutations modulate p85 disruption, lipid binding and kinase activity. The overall consequence of these cis mutations is a greater sensitivity to PI3Kα inhibitors in preclinical models and in the clinic. They analysed Pik3ca mutation from SANDPIPER,4.Baselga J. Dent S.F. Cortés J. et al.Phase III study of taselisib (GDC-0032) + fulvestrant (FULV) v FULV in patients (pts) with estrogen receptor (ER)-positive, PIK3CA -mutant (MUT), locally advanced or metastatic breast cancer (MBC): Primary analysis from SANDPIPER.JCO. 2018; 36 (LBA100): LBA1006doi:10.1200/JCO.2018.36.18_suppl.LBA1006Crossref Google Scholar a phase III clinical trial that tested the efficacy of fulvestrant±taselisib in patients with metastatic luminal BC. They confirmed that multiple-Pik3ca mutations might achieve higher clinical benefit compared with those with single mutations. According to these data, the presence of a double Pik3ca mutation could confer better sensitivity to specific PI3K inhibitors. The revolution of cancer treatment in the last years has highlighted the important role of immunotherapy in several solid tumours. Nevertheless, despite a great effort to better select patients with cancer who will benefit from this approach, no biomarkers have been so far detected. In a recent article published in Nature Medicine, Liu et al examined a cohort of patients with advanced melanoma to discover biomarkers related with response and resistance, trying to understand differential biological features responsible for sensitivity to anti-PD in tumours with and without previous anti-CTLA4 therapy. This investigation was aiming to develop clinically applicable parsimonious predictive models.5.Liu D. Schilling B. Liu D. et al.Integrative molecular and clinical modeling of clinical outcomes to PD1 blockade in patients with metastatic melanoma.Nat Med. 2019; 25: 1916-1927doi:10.1038/s41591-019-0654-5Crossref PubMed Scopus (294) Google Scholar A homogeneous cohort of patients with advanced melanoma was treated with anti-PD1 monotherapy for whom whole exome sequencing and RNA-sequencing was available. According to the current knowledge, tumour mutation burden, tumour-infiltrating lymphocyte and other immune-related signatures were evaluated. In this analysis of 144 patients, major histocompatibility complex (MHC) class II expression, tumour heterogeneity, purity and ploidy were associated with immunotherapy response. The relation between MHC-II and checkpoint inhibitors confirmed that those tumours could stimulate CD4+ helper T-cell or cytotoxic activity.6.Rodig S.J. Gusenleitner D. Jackson D.G. et al.Mhc proteins confer differential sensitivity to CTLA-4 and PD-1 blockade in untreated metastatic melanoma.Sci Transl Med. 2018; 10 (eaar3342)doi:10.1126/scitranslmed.aar3342Crossref PubMed Scopus (283) Google Scholar, 7.Johnson D.B. Estrada M.V. Salgado R. et al.Melanoma-Specific MHC-II expression represents a tumour-autonomous phenotype and predicts response to anti-PD-1/PD-L1 therapy.Nat Commun. 2016; 7 (10582)doi:10.1038/ncomms10582Crossref Scopus (296) Google Scholar One of the major objectives of the study was the evaluation of changes observed after previous treatment with CTLA4 inhibitors. Whether anti-CTLA4 induces or reveals an immune-resistant state in a subset of melanomas is an important question that deserves study. Notably, in this experiment, it was found that previous exposure to anti-CTLA4 did influence those predictors of sensitivity to anti-PD1, although patients with and without exposure had similar response rates to anti-PD1. Postipilimumab tumours with poor immune response at progression were resistant to further anti-PD1. To complete this analysis, the authors constructed predictive models integrating clinical, genomic and transcriptomic characteristics to identify patients with melanoma with intrinsic resistance to anti- PD1. Integrating multiple clinical and molecular features resulted in superior discrimination compared with models with a single feature or modality. In this context, patients treated with ipilimumab, low MHC-II expression and high Lactate dehydrogenase (LDH) predicted intrinsic resistance, whereas lymph node metastasis predicted improved response to therapy. MHC-II and LDH have previously been implicated in predicting anti-PD1 responsiveness.8.Weide B. Martens A. Hassel J.C. et al.Baseline biomarkers for outcome of melanoma patients treated with pembrolizumab.Clin Cancer Res. 2016; 22: 5487-5496doi:10.1158/1078-0432.CCR-16-0127Crossref PubMed Scopus (401) Google Scholar Lymph node metastases might provide a reservoir of tumour-specific immune cells, facilitating their activation by physiological lymph node function.9.Blank C.U. Rozeman E.A. Fanchi L.F. et al.Neoadjuvant versus adjuvant ipilimumab plus nivolumab in macroscopic stage III melanoma.Nat Med. 2018; 24: 1655-1661doi:10.1038/s41591-018-0198-0Crossref PubMed Scopus (406) Google Scholar All these findings will require further validations in independent and larger cohorts. Moreover, the evaluation of heterogeneity represents a limitation to standardise the proposed model. Nevertheless, multimodal data analyses are necessary to progress in our understanding of melanoma sensitivity to PD1 blockade. The oncogenic role of activating mutations in RAS genes is known for more than twenty years. Point mutations of KRAS will induce a constitutively activated status making the KRAS proteins to remain in a Guanosine-5'-triphosphate(GTP)-bound active state, leading to a permanent activation of multiple downstream effectors able to transmit oncogenic signals which eventually produce cancer cell growth and metastases. The conformational changes induced by those mutations have been largely considered as undruggable for a long period of time, although this is not the case anymore. In an inspiring manuscript published in Cancer Discovery, Hallin et al characterised MRTX849, a selective potent and covalent inhibitor of KRASG12C, with significant activity in a series of in vitro and in vivo models, elucidating its mechanisms of response and resistance with responses seen in patients, as well as identifying effective combinations with other anticancer targeted agents, paving the way for a rational clinical development of this type of novel anticancer drugs.10.Hallin J. Engstrom L.D. Hargis L. et al.The KRASG12C Inhibitor MRTX849 Provides Insight toward Therapeutic Susceptibility of KRAS-Mutant Cancers in Mouse Models and Patients.Cancer Discov. 2020; 10: 54-71doi:10.1158/2159-8290.CD-19-1167Crossref PubMed Scopus (543) Google Scholar MRTX849 presented favourable drug-like properties and selectively modified mutant cysteine 12 in GDP bound RASG12C, inhibiting KRAS-dependent signalling. Moreover, this agent showed pronounced cell growth inhibition in almost two-thirds of all KRASG12C-positive cell lines, as well as in patient-derived xenograft models from lung and colon carcinomas. KRAS was almost completely inhibited in vivo by this experimental compound. MRTX849 was also shown to induce some responses in patients with RASG12C mutant adenocarcinomas of the lung included in dose-escalation phase I trials. The most commonly observed mechanisms of resistance were activation of receptor tyrosine kinases, bypass of KRAS dependence and genetic dysregulation of the cell cycle. When RTX849 was combined with Epidermal Growth Factors Receptors (HER) family inhibitors such as afatinib, or PI3K–mTOR or SHP2 inhibitors in resistant models to KRAS inhibition, sensitivity was restored, indicating potentially cotargetable vulnerabilities in these different pathways and supporting trials in which RAS-specific inhibitors could be combined with other targeted agents. As stated by a comment in the same journal, some challenges have still to be faced to properly implement the use of these specific RAS inhibitors.11.Klempner S.J. Hata A.N. Can the Help Match the Hype? KRASG12C-Specific Inhibitors and Beyond.Cancer Discov. 2020; 10: 20-22doi:10.1158/2159-8290.CD-19-1255Crossref PubMed Scopus (10) Google Scholar The most relevant questions remaining are if the maximal activity of these compounds will be achieved in monotherapy or in combination with some other agents, which combinations will be the most effective and in which patient subsets, and how the duration of responses could be compared with current therapies as combination chemotherapy or immune checkpoint inhibition.
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