Integrated CRISPR screening and drug profiling identifies combination opportunities for EGFR, ALK, and BRAF/MEK inhibitors

Anti-tumor efficacy of targeted therapies is variable across patients and cancer types. Even in patients with initial deep response, tumors are typically not eradicated and eventually relapse. To address these chal-lenges, we present a systematic screen for targets that limit the anti-tumor efficacy of EGFR and ALK inhib-itors in non-small cell lung cancer and BRAF/MEK inhibitors in colorectal cancer. Our approach includes genome-wide CRISPR screens with or without drugs targeting the oncogenic driver (anchor therapy), and large-scale pairwise combination screens of anchor therapies with 351 other drugs. Interestingly, target-ing of a small number of genes, including MCL1, BCL2L1, and YAP1, sensitizes multiple cell lines to the respective anchor therapy. Data from drug combination screens with EGF816 and ceritinib indicate that da-satinib and agents disrupting microtubules act synergistically across many cell lines. Finally, we show that a higher-order-combination screen with 26 selected drugs in two resistant EGFR-mutant lung cancer cell lines identified active triplet combinations.

Automated summary

By conducting genome-wide CRISPR screens and large-scale pairwise combination screens, we have identified certain genes, such as MCL1, BCL2L1, and YAP1, that can enhance the sensitivity of lung cancer and colorectal cancer cells to specific drugs, thereby improving therapeutic efficacy. Additionally, through drug combination screens, we have discovered synergistic effects of various drugs across multiple cell lines and identified active triplet combinations for EGFR-mutant lung cancer cells.